There are several syndromes with abnormal susceptibility to infections which seem to have a genetic basis, but for which no linkage studies or gene candidate evaluations have been done. In collaboration with investigators at NIAID, particularly Dr. S. Holland, we have undertaken studies to elucidate the genetic cause of two disorders. The first is a newly recognized susceptibility to Mycobacterium Avium infections, occurring in males in an extended kindred in with an apparently X-linked inheritance pattern. We have determined that the monocytes of affected individuals fail to produce IL-12, an important inducer of interferon which in turn activates macrophages to kill ingested mycobacteria. A carrier test for females has been designed and linkage studies are under way. A second disease under study is the Hyper IgE syndrome, also known as Job's syndrome, in which affected individuals are susceptible to recurrent skin and lung infections and have extreme elevations of IgE. In evaluating sporadic patients and families with multiple affected members we have noted that features of the syndrome other than the susceptibiity to infection exist, and that the mode of inheritance is autodomal dominant with variable expressivity and penetrance. A genome-wide linkage search is planned.